Adaptive responses to sepsis are necessary to prevent organ failure and death. Cellular signaling responses that limit cell death and structural damage allow a cell to withstand insult from sepsis to prevent irreversible organ dysfunction. One such protective pathway to reduce hepatocellular injury is the up‐regulation of heme oxygenase‐1 (HO‐1) signaling. HO‐1 is up‐regulated in the liver in response to multiple stressors, including sepsis and lipopolysaccharide (LPS), and has been shown to limit cell death. Another recently recognized rudimentary cellular response to injury is autophagy. The aim of these investigations was to test the hypothesis that HO‐1 protects against hepatocyte cell death in experimental sepsis in vivo or LPS in vitro via induction of autophagy. These data demonstrate that both HO‐1 and autophagy are up‐regulated in the liver after cecal ligation and puncture (CLP) in C57BL/6 mice or in primary mouse hepatocytes after treatment with LPS (100 ng/mL). CLP or LPS results in minimal hepatocyte cell death. Pharmacological inhibition of HO‐1 activity using tin protoporphyrin or knockdown of HO‐1 prevents the induction of autophagic signaling in these models and results in increased hepatocellular injury, apoptosis, and death. Furthermore, inhibition of autophagy using 3‐methyladenine or small interfering RNA specific to VPS34, a class III phosphoinositide 3‐kinase that is an upstream regulator of autophagy, resulted in hepatocyte apoptosis in vivo or in vitro. LPS induced phosphorylation of p38 mitogen‐activated protein kinase (p38 MAPK), in part, via HO‐dependent signaling. Moreover, inhibition of p38 MAPK prevented CLP‐ or LPS‐induced autophagy. Conclusion: Sepsis or LPS‐induced autophagy protects against hepatocellular death, in part via an HO‐1 p38 MAPK‐dependent signaling. Further investigations are needed to elucidate how autophagic signaling prevents apoptosis and cell death. (HEPATOLOGY 2011;)